The overall objective of this project is to elucidate the mechanisms by which the nuclear receptors nor-1 and nur77 function as tumor suppressors to prevent the development of myeloid leukemia. Nur77 and nor-1 are members of the NR4A subfamily of nuclear receptor transcription factors. NR4A receptors have highly homologous amino acid sequences and can interact with common cis-acting DNA elements to regulate overlapping target genes. Unlike most nuclear receptors, NR4A subfamily members are not ligand activated and can function as constitutively active transcription factors. In addition, they are products of immediate early genes whose expression and activity are regulated in a cell specific manner in response to a variety of extracellular mitogenic, apoptotic and differentiative stimuli. In order to elucidate the essential physiological roles of NR4A receptors, we have generated null mutant mice in which the expression of these proteins has been ablated. The current proposal is based on our recent discovery that mice deficient in both nur77 and nor-1 develop rapidly lethal myeloid leukemia that is nor1/nur77 gene dosage dependent in its latency of development and most closely resembles the acute phase of chronic myeloid leukemia (CML). We hypothesize that nor1 and nur77 are essential tumor suppressor transcription factors operating most likely in hematopoietic stem (HSCs) or downstream myeloid progenitor cells and exert their effects by communication with cell cycle components to regulate the balance between serf renewal, proliferation and cell survival. We further hypothesize that inactivation of nor1/nur77 may play a key role in driving progression of chronic myeloproliferative disease to acute phase. To test this hypothesis, we will 1) continue to examine the cellular mechanisms of initiation and progression of myeloid leukemia in nor1/nur77 null mutant mice, 2) identify the nor1/nur77 dependent molecular genetic signaling pathways that control myelopoietic cell development, 3) determine whether loss of nor1/nur77 cooperates with BCR-ABL oncogenic signaling to drive acute phase progression in a mouse model of CML, and 4) determine whether transgenic targeting of nor1 and nur77 to myeloid progenitor cells is sufficient to rescue the leukemic phenotype in nor1/nur77 null mice. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA111411-01A1
Application #
7050049
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Mufson, R Allan
Project Start
2006-01-18
Project End
2010-12-31
Budget Start
2006-01-18
Budget End
2006-12-31
Support Year
1
Fiscal Year
2006
Total Cost
$266,250
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Zhou, L; Ruvolo, V R; McQueen, T et al. (2013) HDAC inhibition by SNDX-275 (Entinostat) restores expression of silenced leukemia-associated transcription factors Nur77 and Nor1 and of key pro-apoptotic proteins in AML. Leukemia 27:1358-68
Ramirez-Herrick, Ashley M; Mullican, Shannon E; Sheehan, Andrea M et al. (2011) Reduced NR4A gene dosage leads to mixed myelodysplastic/myeloproliferative neoplasms in mice. Blood 117:2681-90
Sirin, Olga; Lukov, Georgi L; Mao, Rui et al. (2010) The orphan nuclear receptor Nurr1 restricts the proliferation of haematopoietic stem cells. Nat Cell Biol 12:1213-9
Zhao, Yue; Howatt, Deborah A; Gizard, Florence et al. (2010) Deficiency of the NR4A orphan nuclear receptor NOR1 decreases monocyte adhesion and atherosclerosis. Circ Res 107:501-11
Nomiyama, Takashi; Zhao, Yue; Gizard, Florence et al. (2009) Deficiency of the NR4A neuron-derived orphan receptor-1 attenuates neointima formation after vascular injury. Circulation 119:577-86
Mullican, Shannon E; Zhang, Shuo; Konopleva, Marina et al. (2007) Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nat Med 13:730-5